Project Summary Sleep apnea (SA) affects ~15% of the US population. Most people with SA develop neurogenic hypertension (HTN) associated with elevated sympathetic nerve activity (SNA). During the previous funding cycle, we modeled SA HTN by exposing rats to chronic intermittent hypoxia (CIH). We determined that HTN induced by 7 days of CIH is maintained by pre-sympathetic PVN neuronal discharge driven by exaggerated NMDA receptor (NMDAR) tone. Importantly, we discovered that PVN activation by CIH involves local adaptive responses (i.e., plasticity) wherein expression of neuronal NMDAR subunits (GluN1 & GluN2B) is reduced and expression of the glial L-glutamate (L-Glu) transporter EEAT2 is increased. These responses reflect homeostatic adaptations to exaggerated glutamatergic input, which we postulate arises, at least in part, from the hindbrain NTS (Project 1) and the forebrain MnPO (Project 2). CIH also decreased PVN expression of the adaptor protein PSD95 that forms a ternary complex with the NMDAR GluN2B subunit and neuronal nitric oxide (NO) synthase (nNOS). This complex couples NMDAR Ca2+ influx with production of NO. We hypothesize that these adaptations to CIH have two offsetting actions. (1) Reduced NMDAR and increased EAAT2 expression blunt glutamatergic PVN activation and thereby buffer development of HTN. (2) Reduced PSD95 blunts NMDAR-driven NO production and lessens its tonic facilitation of GABA release. This disinhibits the PVN and thereby supports development of HTN. The net effect of these opposing adaptations is that HTN induced by CIH is less pronounced than it would be in their absence. In addition to HTN, SA increases the risk of ischemic stroke by ~4 fold. The same PVN adaptations to SA/CIH that participate in development of HTN are hypothesized to reduce ischemic injury by limiting the rise of extracellular L-Glu and reducing the production of neurotoxic NO. Studies in this revised proposal will expose rats to 7 and 28 days of CIH and CIH with hypercapnia (CIHHC) to more closely model human SA. Our specific aims will: (1) Determine effects of CIH & CIHHC on neurogenic HTN, PVN expression of synaptic/excitotoxic signaling proteins and PVN neuronal/tissue survival after local ischemia. (2) Determine effects of CIH/CIHHC adaptations on PVN control of SNA/MAP and mechanisms of neuronal vulnerability to local ischemia. (3) Use viral-mediated gene transfer/shRNA knockdown to mimic and rescue specific PVN adaptations and determine their contributions to hypertensive and neuroprotective effects of CIH & CIHHC.